Mutation clocks demonstrate two phases of latency during human Mycobacterium tuberculosis infections

Little is known about the physiology of Mycobacterium tuberculosis during latency. We studied the generation times of latent M. tuberculosis by determining the number of mutations accumulating each year between M. tuberculosis isolated from 25 index tuberculosis (TB) cases and their latently infected household contacts who subsequently developed active TB. Generation times were high in the first year after infection, but thereafter declined exponentially suggesting a non- or slowly-replicating state. Mutations indicative of oxidative stress did not increase with increasing periods of latency suggesting protection against host effecter mechanisms. Drugs that target replicating bacilli are likely to be effective principally for treating early latency. Therapeutic regimens against late latency may need to be modified for increased activity against quiescent bacteria.